Synthesis and Characterization of NCAs

Streamlined Synthesis of PEG-Polypeptides Directly from Amino Acids

“…We have demonstrated that well-defined polypeptides with controlled MWs and low dispersity can be synthesized in a streamlined manner in the presence of AS via nonpurified NCA intermediate prepared from amino acid phosgenation, the so-called Fuchs-Farthing method. , Leuchs method, using N -alkoxycarbonyl α-amino acids with halogenating reagents, is also widely utilized for the preparation of NCAs. ,, During the synthesis, however, various hydrophobic impurities (e.g., alkyl halide, Figure a) are formed and therefore the resulting NCAs in poor purities are nonusable for controlled polypeptide synthesis; , the clean NCAs suitable for polymerization after recrystallization or other purification steps are often in suboptimal yields. For amino acids with complex side-chain functionalities, they are often in its N α -alkoxycarbonyl form that can only be subject to the Leuchs method for NCA preparation.…”

“…Controlled NCA polymerizations by PEG-amine or amine derivatives have been reported with special techniques, such as under high vacuum, , under nitrogen flowing, at low temperature, , using ammonium salts, , amine-borane Lewis pairs, or PEG-amine-trimethylsilylcarbamate. , Besides the drawbacks of stringent polymerization setup and slow polymerization rates, all of these methods require the use of ultrapure NCA monomers obtained through tedious, multistep crystallization, or column purification under inert gas protection. − Otherwise, the acidic and electrophilic impurities generated during NCA synthesis would inhibit the polymerization by protonating or reacting with the amine initiators. ,, Despite the recent development of simplified strategies of NCA synthesis and purification, , its handling and subsequent polymerization still impose significant challenges to nonexperts, limiting the broad applications of polypeptide materials. In addition, synthesis, storage, and polymerization of NCAs all require water-free conditions due to their instability to water, further complicating the handling of NCA monomers .…”

An Expeditious Multigram‐Scale Synthesis of Lysine Dendrigraft (DGL) Polymers by Aqueous N‐Carboxyanhydride Polycondensation

“…www.chemeurj.org sensitivity to hydrolysis, NCAs [20,21] are nowadays predominantly reacted in aprotic solvents under strictly anhydrous conditions, whereas earlier studies (in the 1950s) conducted in aqueous media [22][23][24][25] were later abandoned because simultaneous NCA hydrolysis was considered to be deleterious to the control of NCA polycondensation. Reinvestigating Bartletts works, our group observed that NCA aminolysis occurs 100 times faster than NCA hydrolysis in weakly acidic aqueous media (pH 5-6.5).…”

“…Furthermore, G1P indeed meets the minimum DP of > 7-10 required for peptides to ensure sufficient thermodynamic stability of b-sheet aggregates in neutral aqueous medium. [20] In further generations (e.g., ! 2), the formation of welldefined b-sheet aggregates from GnP is impossible because of the branched structure of the polymers.…”

Highly Productive Continuous Flow Synthesis of Di- and Tripeptides in Water

“…The reason that pH 10.2 has been found to be optimal becomes clear: the NCA p K a is 11.3, so this pH keeps the reactive anion concentration low, while the amino acid p K a is 9.2, keeping the concentration of the free amine high. The reactivity of NCAs has been discussed in detail by Kricheldorf and includes their use in the formation of homopolypeptides . Bartlett studied the kinetics of NCA hydrolysis and estimated the rate to be one-third that of the amino acid at the same pH, both rates being above 1.6 × 10 6 M –1 ·s –1 . , Caplow and Johnson each showed the intermediate carbamic acid is unstable above 0 °C (a problem in water) and can prematurely decarboxylate to the free amino acid with a rate constant of >9* 10 7 M –1 ·s –1 for glycine at pH 10, , leading to an unwanted tripeptide, Figure .…”